Epicutaneous immunotherapy for the treatment of peanut allergy in children and young adults. Journal of Allergy and Clinical Immunology
BACKGROUND: Peanut allergy is common, life-threatening, and without therapeutic options. We evaluated peanut epicutaneous immunotherapy (EPIT) by using Viaskin Peanut for peanut allergy treatment. OBJECTIVE: We sought to evaluate the clinical, safety, and immunologic effects of EPIT for the treatment of peanut allergy. METHODS: In this multicenter, double-blind, randomized, placebo-controlled study, 74 participants with peanut allergy (ages 4-25 years) were treated with placebo (n = 25), Viaskin Peanut 100 μg (VP100; n = 24) or Viaskin Peanut 250 μg (VP250; n = 25; DBV Technologies, Montrouge, France). The primary outcome was treatment success after 52 weeks, which was defined as passing a 5044-mg protein oral food challenge or achieving a 10-fold or greater increase in successfully consumed dose from baseline to week 52. Adverse reactions and mechanistic changes were assessed. RESULTS: At week 52, treatment success was achieved in 3 (12%) placebo-treated participants, 11 (46%) VP100 participants, and 12 (48%) VP250 participants (P = .005 and P = .003, respectively, compared with placebo; VP100 vs VP250, P = .48). Median change in successfully consumed doses were 0, 43, and 130 mg of protein in the placebo, VP100, and VP250 groups, respectively (placebo vs VP100, P = .014; placebo vs VP250, P = .003). Treatment success was higher among younger children (P = 0.03; age, 4-11 vs >11 years). Overall, 14.4% of placebo doses and 79.8% of VP100 and VP250 doses resulted in reactions, predominantly local patch-site and mild reactions (P = .003). Increases in peanut-specific IgG4 levels and IgG4/IgE ratios were observed in peanut EPIT-treated participants, along with trends toward reduced basophil activation and peanut-specific TH2 cytokines. CONCLUSIONS: Peanut EPIT administration was safe and associated with a modest treatment response after 52 weeks, with the highest responses among younger children. This, when coupled with a high adherence and retention rate and significant changes in immune pathways, supports further investigation of this novel therapy.
Enhanced Prophylactic and Therapeutic Effects of Polylysine-Modified Ara h 2 DNA Vaccine in a Mouse Model of Peanut Allergy.
BACKGROUND: The prevalence of food allergy has been increasing, but treatment is very limited. DNA vaccination has been recognized as a promising method for the treatment of allergic diseases; however, poor immunogenicity has hindered its application. METHODS: BALB/c mice were intradermally injected with plasmid DNA encoding the peanut protein Ara h 2 (pAra h 2) or pAra h 2 pretreated with poly-L- lysine (PLL) before or after sensitization with Ara h 2 protein. Ara h 2-specific antibodies were measured by ELISA. CD207+ dendritic cells (DCs) and Treg cells in draining lymph nodes were analyzed by flow cytometry after DNA immunization, and cytokine production in splenocytes was also analyzed. RESULTS: In the prophylactic study, pretreatment with pAra h 2 or PLL-pAra h 2 resulted in lower levels of Ara h 2-specific IgG1, IgG2a, and IgE after sensitization with Ara h 2 protein, and mice in the PLL-pAra h 2 group had a significantly lower level of antibodies than those in the pAra h 2 group. In the treatment study, intradermal injection with pAra h 2 or PLL-pAra h 2 after Ara h 2 protein sensitization significantly decreased the level of Ara h 2-specific antibodies, and PLL- pAra h 2 had stronger effects than pAra h 2. There were increased numbers of CD207+ DCs and Treg cells in the mice receiving intradermal injection with PLL-pAra h 2, and splenocytes from PLL-pAra h 2-treated mice secreted increased levels of IFN-γ and IL-10. CONCLUSIONS: Modification of pAra h 2 with PLL improved its prophylactic and therapeutic effects in peanut-allergic mice.
Desensitization for Peanut Allergies in Children.
Immunotherapy for peanut allergy has been an exploding topic of study within the last few years. Sublingual, epicutaneous, and oral immunotherapy are being investigated and show promise in the treatment of peanut allergy. Oral immunotherapy has shown the most clinical benefit; however, sublingual and epicutaneous immunotherapy appear to have the most favorable safety profiles. Most studies to date suggest that only a minority of subjects achieve sustained unresponsiveness to peanut after discontinuation of immunotherapy. Recent efforts have been focused on identifying adjunct therapies, such as omalizumab, that may assist patients in achieving peanut desensitization more quickly and with greater success. Several underlying immunologic mechanisms, including a switch from IgE to IgG4 production and induction of T regulatory cells, have been studied although more research is needed to identify reliable biomarkers. This article will describe the immunotherapy approaches that are being investigated to induce peanut desensitization, and highlight the benefits and risks of these therapies that need to be considered before they are ready for routine clinical practice.
Threshold Dose Distribution in Walnut Allergy.
BACKGROUND: In food allergy, eliciting doses (EDs) of foods on a population level can improve risk management and labeling strategies for the food industry and regulatory authorities. Previously, data available for walnut were unsuitable to determine EDs. OBJECTIVE: The objective of this study was to determine EDs for walnut allergic adults and to compare with previously established threshold data for peanut and tree nuts. METHODS: Prospectively, adult subjects with a suspected walnut allergy underwent a low-dose double-blind, placebo-controlled food challenge. Individual no observed and lowest observed adverse effect levels were determined and log-normal, log-logistic, and Weibull models were fit to the data. Estimated ED values were calculated for the ED5, ED10, and ED50, the dose respectively predicted to provoke an allergic reaction in 5%, 10%, and 50% of the walnut allergic population. RESULTS: Fifty-seven subjects were challenged and 33 subjects were confirmed to be walnut allergic. Objective symptoms occurred in 20 of the positive challenges (61%). The cumulative EDs in the distribution models ranged from 3.1 to 4.1 mg for the ED05, from 10.6 to 14.6 mg walnut protein for the ED10, and from 590 to 625 mg of walnut protein for the ED50. CONCLUSIONS: Our data indicate that population EDs for walnut are slightly higher compared with those for peanut and hazelnut allergy. Currently available data indicate that the ED values for hazelnut could be used as a conservative temporary placeholder when implementing risk management strategies for other tree nuts where little or no food challenge data are available.
No difference in health-related quality of life, after a food challenge with cashew nut in children participating in a clinical trial.
BACKGROUND: Previous studies showed that Health-Related Quality of Life (HRQL) significantly improved after the food challenge, with greater improvements in HRQL after a negative outcome than a positive outcome. It is currently unknown whether this also occurs in patients undergoing DBPCFCs with cashew nut in the context of a clinical trial. METHODS: Quality of life was studied in children enrolled in a cashew nut study using food allergy quality of life questionnaires (FAQLQs). Children, teenagers and parents of the children completed the questionnaires before the challenge test and 6 months after the DBPCFC with cashew nut. The difference in the change in HRQL between the children with a positive and negative DBPCFC outcome was studied by Mann-Whitney U test. RESULTS: In total 112 children (67 boys, median age 9 yrs.) were included. The children, teenagers and parents of the children completed in total 143 sets of questionnaires. There were no significant differences in baseline total and domain scores compared to the follow-up scores in the FAQLQ-CF, -TF and -PF. In children, the delta FAIM score in the negative DBPCFC tested group was significantly better than the delta FAIM score in the positive challenged group (p= 0.026). There were no significant differences in the changes in the scores of the FAQLQ-CF and FAQLQ-PF in the children with a positive challenge outcome, compared to the children with a negative challenge result. However, there was a significant difference in the change in score between the latter groups in the domain 'accidental exposure' of the FAQLQ-TF (p=0.049). CONCLUSION: This study showed no difference in change of HRQL scores after a DBPCFC with cashew nut in children participating in a clinical trial. The utility of HRQL as an outcome for clinical trials in food allergy may be limited if participant baseline HRQL is relatively unimpaired. This article is protected by copyright.
Association of tree nut and coconut sensitization.
BACKGROUND: Coconut (Cocos nucifera), despite being a drupe, was added to the US Food and Drug Administration list of tree nuts in 2006, causing potential confusion regarding the prevalence of coconut allergy among tree nut allergic patients. OBJECTIVE: To determine whether sensitization to tree nuts is associated with increased odds of coconut sensitization. METHODS: A single-center retrospective analysis of serum specific IgE levels to coconut, tree nuts (almond, Brazil nut, cashew, chestnut, hazelnut, macadamia, pecan, pistachio, and walnut), and controls (milk and peanut) was performed using deidentified data from January 2000 to August 2012. Spearman correlation (ρ) between coconut and each tree nut was determined, followed by hierarchical clustering. Sensitization was defined as a nut specific IgE level of 0.35 kU/L or higher. Unadjusted and adjusted associations between coconut and tree nut sensitization were tested by logistic regression. RESULTS: Of 298 coconut IgE values, 90 (30%) were considered positive results, with a mean (SD) of 1.70 (8.28) kU/L. Macadamia had the strongest correlation (ρ = 0.77), whereas most other tree nuts had significant (P < .05) but low correlation (ρ < 0.5) with coconut. The adjusted odds ratio between coconut and macadamia was 7.39 (95% confidence interval, 2.60-21.02; P < .001) and 5.32 (95% confidence interval, 2.18-12.95; P < .001) between coconut and almond, with other nuts not being statistically significant. CONCLUSION: Our findings suggest that although sensitization to most tree nuts appears to correlate with coconut, this is largely explained by sensitization to almond and macadamia. This finding has not previously been reported in the literature. Further study correlating these results with clinical symptoms is planned.
Advances in ultra-high performance liquid chromatography coupled to tandem mass spectrometry for sensitive detection of several food allergens in complex and processed foodstuffs.
Sensitive detection of food allergens is affected by food processing and foodstuff complexity. It is therefore a challenge to detect cross-contamination in food production that could endanger an allergic customer's life. Here we used ultra-high performance liquid chromatography coupled to tandem mass spectrometry for simultaneous detection of traces of milk (casein, whey protein), egg (yolk, white), soybean, and peanut allergens in different complex and/or heat-processed foodstuffs. The method is based on a single protocol (extraction, trypsin digestion, and purification) applicable to the different tested foodstuffs: chocolate, ice cream, tomato sauce, and processed cookies. The determined limits of quantitation, expressed in total milk, egg, peanut, or soy proteins (and not soluble proteins) per kilogram of food, are: 0.5mg/kg for milk (detection of caseins), 5mg/kg for milk (detection of whey), 2.5mg/kg for peanut, 5mg/kg for soy, 3.4mg/kg for egg (detection of egg white), and 30.8mg/kg for egg (detection of egg yolk). The main advantage is the ability of the method to detect four major food allergens simultaneously in processed and complex matrices with very high sensitivity and specificity.
Experimental food allergy to peanut enhances the immune response to house dust mite in the airways of mice.
BACKGROUND: Food allergy has been associated with an increased risk for the development of allergic asthma. Asthma is a risk factor for the development of an anaphylactic response to food allergens. An immunological interplay between sensitization to different allergens in different compartments of the body might be involved. OBJECTIVE: To evaluate the immunological interplay between intragastrical peanut (PE) sensitization and respiratory sensitization to house dust mite (HDM) allergens. METHODS: BALB/c mice were intra-gastrically sensitized to peanut or sham-sensitized and challenged systemically to PE. Between sensitization and challenge, mice were intranasally exposed to HDM extract or PBS, as a control. The response to HDM (eosinophil recruitment, cytokine response, HDM specific immunoglobulins, and airway hyperreactivity) and to PE (cytokine response, mast cells in gut, mMCP-1 in serum, body temperature) was assessed. RESULTS: A preceding PE sensitization increased HDM induced production of IL-4, IL-5, IL-13 and IFNγ in lung draining lymph nodes and total IgE levels in HDM sensitized mice. However, recruitment of inflammatory cells to the airways or airway hyperreactivity was not aggravated in PE/HDM double-sensitized mice. Alternatively, HDM induced airway inflammation did not significantly affect the immune response or the anaphylactic response to a systemic challenge with peanut. CONCLUSION AND CLINICAL RELEVANCE: Our data show that a preceding peanut sensitization boosted IgE and HDM-specific Th2 response in the airways in mice. It contributes to the understanding of the underlying immunological mechanism of polysensitization which often occurs in allergic individuals over time.
Three peanut allergic/sensitized phenotypes with gender difference.
BACKGROUND: Peanut allergic reactions are heterogeneous ranging from mild symptoms to anaphylaxis. OBJECTIVE: Identify peanut allergic/sensitized phenotypes to personalize patient management. METHODS: A combined factor and cluster analysis was used to study the phenotypes of 696 patients diagnosed with peanut sensitization and enrolled in the MIRABEL survey. The method was first applied to the 247 patients with an Oral Food Challenge (OFC). It was then applied to the 449 patients without OFC to confirm the findings in an independent population. RESULTS: Three independent clusters emerged from the OFC subgroup. Cluster 1, "Severe peanut allergy with little allergic multimorbidity" (123 subjects), had the highest proportion of patients with positive OFC (92%), a medium level of peanut protein inducing a positive OFC (235 mg), lower percentage of allergic multimorbidity (2% asthma plus atopic dermatitis (A+AD), no cases of A+AD + multiple food allergies (MFA)). Cluster 2, "Severe peanut allergy with frequent allergic multimorbidity" (62 subjects), had a high proportion of patients with positive OFC (85%) with the lowest level of peanut protein inducing a positive OFC (112mg), 89% allergic subjects, 100% with allergic multimorbidity (A+AD) and 84% with A+AD+MFA. Cluster 3, "Mild peanut allergic/sensitized phenotype" (62 subjects), had the lowest mean age, the lowest proportion of patients with positive OFC (53%) with a high level of peanut protein inducing a positive OFC (770 mg), a low percentage of allergic multimorbidity (48% A+AD+MFA). The two severe peanut allergy phenotypes were more frequent in girls. The same clusters were found in the subgroup of patients without OFC. CONCLUSION & CLINICAL RELEVANCE: Besides the classic markers associated with lower threshold doses of OFC (such as SPT and rAra h2), allergic multimorbidity and female gender should also be taken into account to better adapt the progressive dosage of provocation tests.
Global perceptions of food allergy thresholds in 16 countries.
Background: Food allergy is a growing global health issue that affects daily life and food purchasing habits. Quality data on the global consumer perspective of food allergy is limited, particularly about thresholds and food labeling risk. Many individuals with food allergy are counseled that small amounts of allergen can potentially cause life-threatening reactions, and to avoid foods with Precautionary Advisory Labeling (PAL). The purpose of this study was to understand attitudes of consumers about food allergy thresholds and food purchasing habits related to PAL in sixteen countries. Methods: A questionnaire was distributed by patient support groups in 16 countries to consumers with food allergy. The questionnaire gathered opinions about food allergy thresholds and PAL purchasing habits. Results: 9,689 respondents from 16 countries completed the survey.19% of respondents stated they would purchase a food containing their allergen if the amount present would not cause a reaction and 3% would purchase a food if the amount of allergen present would cause a mild reaction. When asked about labeling, 16% of respondents reported that they would purchase food with a "may contain" statement, 25% would purchase food labeled "may contain traces of allergen", and 41% would purchase products labeled "manufactured in a facility that also processes allergen". Conclusions: Findings suggest that understanding of food allergen thresholds and precautionary allergen labelling is limited and consumers may develop their own risk assessment based on labels, which are not based on clinical validation. Improved awareness of thresholds, standardization of PAL, and clinical validation are needed globally.